IN A PHASE I trial of patients with advanced solid tumors, the combination of pamiparib (BGB-290), a selective poly (ADP-ribose) polymerase (PARP) inhibitor, and tislelizumab (BGB-A317), an agent targeting the programmed cell death protein 1 (PD-1) receptor, was well tolerated while demonstrating antitumor activity.1 According to data presented at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, 10 patients (23%) had a confirmed complete or partial response, and responses were observed in patients with wild-type and mutant BRCA status.
Linda R. Mileshkin, MBBS
“The combination of tislelizumab and pamiparib was generally well tolerated, with 10 patients on treatment more than 200 days,” said Linda R. Mileshkin, MBBS, Associate Professor at the Peter MacCallum Cancer Centre in Australia. “Although liver-related adverse events were observed in 13 patients, these events were manageable and reversible with corticosteroid treatment. These results support the continuation of this trial with enrollment into disease-specific cohorts.”
As Dr. Mileshkin explained, the rationale for using this combination was the hope that upregulation of tumor-associated antigens with PARP inhibitor treatment would improve the antitumor activity of checkpoint inhibitors. Pamiparib, a potent inhibitor of PARP-1 and PARP-2, has shown promising activity as a single agent and is hypothesized to promote neoantigen release. Tislelizumab, a humanized immunoglobulin G (IgG) 4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the PD-1 receptor and is being developed in (a range of) solid and hematologic malignancies.
Phase I Dose-Escalation Study Details
THIS TWO-PART trial consisted of an initial dose escalation to determine the maximum tolerated dose, safety, pharmacokinetic profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic, and small cell lung cancers. Enrolled patients had to have advanced malignancy with measurable disease, at least one prior treatment, a good performance status (Eastern Cooperative Oncology Group ≤ 1), and no prior PARP or anti–PD-1 therapy.
Enrolled patients were predominantly female (86%) and white (90%), with a median age of 63. Patients were also heavily pretreated, said Dr. Mileshkin, with a median of four prior lines of therapy. Although the majority of cancers were either ovarian, fallopian tube, or peritoneal, a range of other solid tumors were also studied. In addition, BRCA status was assessed locally in 25 patients, of whom 14 had a germline or somatic BRCA 1/2 mutation.
Cohorts of 6 to 12 patients with advanced solid tumors were treated in each of 5 planned dose levels. The investigators concluded that dose level 4 should be used as the recommended phase II dose (tislelizumab at 200-mg infusion every 3 weeks plus pamiparib at 40 mg twice daily).
ALL OF THE 49 patients treated in the initial dose-escalation phase of the study had at least 1 treatment-related adverse event, with serious events seen in 21 patients. These events were fairly evenly split between PARP and PD-1 therapies. Despite the large number of treatment-related adverse events, however, most patients were able to continue therapy, and it was rarely necessary to discontinue both drugs because of toxicity. A total of 11 patients discontinued tislelizumab treatment, 6 patients discontinued pamiparib, and 3 patients discontinued treatment with both drugs due to a treatment-related adverse event.
“These results support the continuation of this trial with enrollment into disease-specific cohorts.”— Linda R. Mileshkin, MBBS
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The most common treatment-related adverse events related to pamiparib included nausea (grades 1/2, 55.1%; grades 3/4, 4.1%), fatigue (38.8% and 4.1%, respectively), diarrhea (20.4% and 0%, respectively), vomiting (12.2% and 2.0%, respectively), and anemia (12.2% and 12.2%, respectively). Most of the treatment-related adverse events linked to tislelizumab were grade 1/2, with fatigue (36.7%), nausea (20.4%), and diarrhea (14.3%) being the most common. There was one grade 3/4 case of fatigue (2.0%) and one case of grade 3 pruritus (2.0%).
Hepatic Adverse Events
AS DR. MILESHKIN reported, 23 patients (46.9%) experienced at least 1 immune-related treatment-related adverse event, and there was a signal concerning hepatic toxicity, with 13 hepatic events reported in the trial, including 9 grade 3/4 events. The median time to onset of events reported was 55 days, which was beyond the initial dose-limiting toxicity period.
“Ten patients had grade 2 or higher transaminitis requiring treatment with corticosteroids, but these patients all recovered promptly,” said Dr. Mileshkin, who noted the subsequent protocol was amended to increase real-time safety monitoring and provide better guidance to the investigators. “Since this amendment, the rate of hepatic events has fallen.”
Treatment Response and Duration
THE OBJECTIVE response rate is currently 20%, including two complete responses (4%) and eight confirmed partial responses (16%). The clinical benefit rate, which included complete and partial responses as well as durable stable disease of at least 24 weeks, was 39%. The median duration of response was 168.5 days.
“Ten patients had a duration of treatment with the combination therapy of more than 200 days,” said Dr. Mileshkin, who also noted that 11 patients remained on treatment at the time of data cutoff.
Although the majority of responses occurred in patients with ovarian cancer and in BRCA-mutant carriers, responses were seen in patients with wild-type status and other disease sites, including those with breast, uterine, and pancreatic cancers, the authors noted. Enrollment of disease-specific cohorts in the second part of this trial is now ongoing. ■
DISCLOSURE: Dr. Mileshkin’s travel and accommodations have been paid for by BeiGene.
1. Friedlander M, Meniawy T, Markman B, et al: A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 in combination with the PARP inhibitor BGB-290 in advanced solid tumors. 2018 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 48. Presented January 25, 2018.
Deborah J.L. Wong, MD, PhD
DISCUSSANT FOR THIS abstract, Deborah J.L. Wong, MD, PhD, of the David Geffen School of Medicine at the University of California, highlighted the preclinical rationale, as well as in vitro and in vivo data, supporting the potential benefit of poly (ADP-ribose)...!-->!-->